Abstract Photodynamic therapy (PDT) has gained much attention as a relatively new cancer treatment modality. PDT has a favorable toxicity profile compared to radiotherapy. Meanwhile, it does not incur resistance, and can be applied to previously irradiated tissues. However, the use of PDT in the clinic has been very limited. This is largely due to its surface-weighted treatment efficacy, a result of limited penetration depth of light in tissues. Our long term objective is to develop a novel PDT derivative called X-ray induced PDT or X-PDT that can break the shallow penetration limitation. Our strategy is to use X-ray, which has great tissue penetration ability, as the energy source to trigger PDT. The key element of our technology is an integrated nanosystem, consisting of a scintillator nanoparticle core and photosensitizing drugs that match the scintillator?s emission wavelength. Upon X-ray irradiation, the nanoparticle scintillator functions as a transducer, converting X-ray photons to visible light photons. The visible photons, in turn, activate the near-by photosensitizing drugs to produce a cytotoxic species called singlet oxygen. Owing to the excellent transmittance of X-ray, X-PDT can be activated from deep tissues. Moreover, it was found that X-PDT is essentially a combination of PDT and radiotherapy. This leads to synergistic treatment outcomes, allowing X-PDT to efficiently kill cancer cells at low radiation doses, even for cancer cells that are refractory to radiotherapy. These characteristics make X-PDT an appealing treatment methodology. The present project will exploit X-PDT to treat non?small cell lung cancer (NSCLC), which is challenging or not possible for conventional PDT. NSCLC accounts for 85% of all lung cancer cases, and is diagnosed in 187,000 persons each year. Radiation, often concurrent with chemotherapy, is the standard of care for the majority of the patients. The treatment, however, may cause severe side effects such as neutropenic fever and Grade 3 esophagitis. Once recur, treatment options are limited since the radiation has been given to the maximum tolerated dose. Hence, there is an urgent need for an effective and less toxic treatment for NSCLC. It is expected that X-PDT can efficiently kill NSCLC through external radiation of relatively low doses with minimal collateral damage. Success of this project will be paradigm-shifting, breaking the shallow penetration dogma of conventional PDT and opening many new possibilities. X-PDT holds great potential in clinical translation, complementing or replacing current treatment regimens for NSCLC therapy. Although the current study is focused on NSCLC, the methodology can be easily extended to treatment of other cancer types, for instance head and neck cancer, breast cancer, and prostate cancer.